Flurbiprofen is a substance used as an antiphlogistic analgetica in the field of medicament, and especially it is known that (S)-flurbiprofen has an excellent efficacy (e.g., U.S. Pat. No. 5,190,981).
The flurbiprofen is generally produced in the form of a racemic compound. It is known that from the racemic compound, flurbiprofen having a high optical purity can be produced by an optical resolution method using, for example, an optically active amine compound (more specific example is α-phenylethylamine) as an optical resolution agent (e.g., Japanese Laid-Open Patent Publication No. 54-154724 and U.S. Pat. No. 4,209,638).
The above-described method using an optical resolution agent utilizes a difference in the physical properties between diastereomers, which are produced from a pair of enantiomer of a racemic flurbiprofen and another optically active substance.
However, with these methods, frequent resolution operations are necessary in order to improve the optical purity of flurbiprofen. For this reason, it was difficult to produce flurbiprofen having a desired optical purity efficiently.
When a racemic substance is subjected to optical resolution, a general rule is not known as to which antipode should be used as an optical resolution agent in order to selectively obtain a salt formed by the resolution agent and a desired enantiomer to provide a slightly soluble crystal. For this reason, in general, it is inevitable to repeat preliminary experiments many times in which various optical resolution agents are combined with various solvents with respect to a substance to be subjected to optical resolution. Therefore, it is very difficult to select a preferable optical resolution agent. Moreover, even if a relatively preferable optical resolution agent is specified in the above-described manner, it is necessary to perform resolution operations frequently. Therefore, there is a demand for development of a more efficient optical resolution method to increase the industrial productivity.